Electrophysiological and behavioral characterization of the sodium leak channel NALCN in dopaminergic neurons
Open AccessNALCN is a sodium leak channel ubiquitously expressed throughout the brain with a critical role in driving pacemaking in numerous neurons. Importantly, NALCN is associated with several neuropsychiatric disorders involving the dopamine system. However, the role of NALCN in driving pacemaking of dopaminergic neurons (DANs) and in dopamine-dependent behaviors has not been fully explored. We tested the role of NALCN in pacemaking of substantia nigra (SNc) and ventral tegmental area (VTA) DANs in male and female mice. We found that pacemaking of retrogradely-labeled VTA DAN subpopulations involves large contributions from NALCN, such that inhibition of NALCN slowed firing by 32 to 71% along a medial-lateral gradient. In contrast, we found that pacemaking of SNc DANs involves overlapping conductances, with a less prominent role of NALCN. Consistent with this, inhibition of NALCN, L-type calcium, or hyperpolarization-activated (HCN) channels alone had no effect on firing in SNc, while simultaneous blockade of NALCN and HCN slowed firing. Additionally, the persistent voltage-gated sodium current and sodium leak current had similar amplitudes during the interspike interval. Finally, we found that in the absence of HCN or NALCN, SNc DANs are more sensitive to shallow hyperpolarizing current injections. Combined, these data suggest that many small currents support pacemaking in the SNc, with NALCN promoting robustness of firing in the presence of perturbation, while NALCN plays a major role in pacemaking in the VTA. When systematically analyzing the behavioral phenotype of male and female mice lacking expression of NALCN in DANs, we found that loss of NALCN from birth results in locomotor hyperactivity, improved motor coordination, increased novelty exploration, and increased psychostimulant sensitization. Loss of NALCN in adulthood results in locomotor hyperactivity and impaired motor coordination. We found no changes in motor learning, anxiety-related behavior, or psychostimulant-induced locomotion following loss of NALCN at either timepoint. Together, these data suggest NALCN in DANs plays a central role in expression of motor behaviors across the lifespan and modulates how an animal explores its environment. These data lay the groundwork for DAN subpopulation specific treatment of neuropsychiatric conditions and for utilization of this animal model to answer future questions about DAN excitability in behavior and disease.
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CobbLewis_gwu_0075A_16282.pdf | 2023-11-14 | Open Access |
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